1. Cell Biology

Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors

  1. Christopher A Natale
  2. Elizabeth K Duperret
  3. Junqian Zhang
  4. Rochelle Sadeghi
  5. Ankit Dahal
  6. Kevin Tyler O'Brien
  7. Rosa Cookson
  8. Jeffrey D Winkler
  9. Todd W Ridky  Is a corresponding author
  1. Perelman School of Medicine, University of Pennsylvania, United States
  2. University of Pennsylvania, United States
https://doi.org/10.7554/eLife.15104
Share this article
Cite this article
  1. Christopher A Natale
  2. Elizabeth K Duperret
  3. Junqian Zhang
  4. Rochelle Sadeghi
  5. Ankit Dahal
  6. Kevin Tyler O'Brien
  7. Rosa Cookson
  8. Jeffrey D Winkler
  9. Todd W Ridky
(2016)
Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors
eLife 5:e15104.
https://doi.org/10.7554/eLife.15104
  2. Download BibTeX
  3. Download .RIS

Abstract

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.

Article and author information

Author details

  1. Christopher A Natale

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    Christopher A Natale, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.

  2. Elizabeth K Duperret

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  3. Junqian Zhang

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  4. Rochelle Sadeghi

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  5. Ankit Dahal

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  6. Kevin Tyler O'Brien

    Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  7. Rosa Cookson

    Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  8. Jeffrey D Winkler

    Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    Jeffrey D Winkler, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.

  9. Todd W Ridky

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    ridky@mail.med.upenn.edu
    Competing interests
    Todd W Ridky, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#803381) of the University of Pennsylvania.

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: February 9, 2016
  2. Accepted: April 11, 2016
  3. Accepted Manuscript published: April 26, 2016 (version 1)
  4. Version of Record published: May 11, 2016 (version 2)

Copyright

© 2016, Natale et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,860
    Page views
  • 1,022
    Downloads
  • 76
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Christopher A Natale
  2. Elizabeth K Duperret
  3. Junqian Zhang
  4. Rochelle Sadeghi
  5. Ankit Dahal
  6. Kevin Tyler O'Brien
  7. Rosa Cookson
  8. Jeffrey D Winkler
  9. Todd W Ridky
(2016)
Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors
eLife 5:e15104.
https://doi.org/10.7554/eLife.15104

Categories and tags

Research organisms

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    Cohesin-independent STAG proteins interact with RNA and R-loops and promote complex loading

    Hayley Porter, Yang Li ... Suzana Hadjur
    Research Article Updated

    Most studies of cohesin function consider the Stromalin Antigen (STAG/SA) proteins as core complex members given their ubiquitous interaction with the cohesin ring. Here, we provide functional data to support the notion that the SA subunit is not a mere passenger in this structure, but instead plays a key role in the localization of cohesin to diverse biological processes and promotes loading of the complex at these sites. We show that in cells acutely depleted for RAD21, SA proteins remain bound to chromatin, cluster in 3D and interact with CTCF, as well as with a wide range of RNA binding proteins involved in multiple RNA processing mechanisms. Accordingly, SA proteins interact with RNA, and R-loops, even in the absence of cohesin. Our results place SA1 on chromatin upstream of the cohesin ring and reveal a role for SA1 in cohesin loading which is independent of NIPBL, the canonical cohesin loader. We propose that SA1 takes advantage of structural R-loop platforms to link cohesin loading and chromatin structure with diverse functions. Since SA proteins are pan-cancer targets, and R-loops play an increasingly prevalent role in cancer biology, our results have important implications for the mechanistic understanding of SA proteins in cancer and disease.

    1. Cell Biology

    Identification of paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis

    Emmeline Marchal-Duval, Méline Homps-Legrand ... Arnaud A Mailleux
    Research Article

    Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-b/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis.

    1. Cell Biology
    2. Neuroscience

    APOE expression and secretion are modulated by mitochondrial dysfunction

    Meghan E Wynne, Oluwaseun Ogunbona ... Victor Faundez
    Research Article Updated

    Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.